View source for 5ufu


==Structure of AMPK bound to activator==
<StructureSection load='5ufu' size='340' side='right'caption='[[5ufu]], [[Resolution|resolution]] 3.45&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5ufu]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus] and [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UFU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5UFU FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.45&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=85V:1,4 3,6-DIANHYDRO-2-O-(6-CHLORO-5-{4-[1-(HYDROXYMETHYL)CYCLOPROPYL]PHENYL}-1H-BENZIMIDAZOL-2-YL)-D-MANNITOL'>85V</scene>, <scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=AMP:ADENOSINE+MONOPHOSPHATE'>AMP</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=STU:STAUROSPORINE'>STU</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5ufu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ufu OCA], [https://pdbe.org/5ufu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ufu RCSB], [https://www.ebi.ac.uk/pdbsum/5ufu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ufu ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/AAPK1_RAT AAPK1_RAT] Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Regulates lipid synthesis by phosphorylating and inactivating lipid metabolic enzymes such as ACACA, ACACB, GYS1, HMGCR and LIPE; regulates fatty acid and cholesterol synthesis by phosphorylating acetyl-CoA carboxylase (ACACA and ACACB) and hormone-sensitive lipase (LIPE) enzymes, respectively. Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3. AMPK stimulates glucose uptake in muscle by increasing the translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane, possibly by mediating phosphorylation of TBC1D4/AS160. Regulates transcription and chromatin structure by phosphorylating transcription regulators involved in energy metabolism such as CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A. Acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm. In response to stress, phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote transcription. Acts as a key regulator of cell growth and proliferation by phosphorylating TSC2, RPTOR and ATG1: in response to nutrient limitation, negatively regulates the mTORC1 complex by phosphorylating RPTOR component of the mTORC1 complex and by phosphorylating and activating TSC2. In response to nutrient limitation, promotes autophagy by phosphorylating and activating ULK1. AMPK also acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to destabilize it. May regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize it. Also has tau-protein kinase activity: in response to amyloid beta A4 protein (APP) exposure, activated by CAMKK2, leading to phosphorylation of MAPT/TAU; however the relevance of such data remains unclear in vivo. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1.<ref>PMID:2369897</ref> <ref>PMID:9029219</ref> <ref>PMID:10025949</ref> <ref>PMID:11069105</ref> <ref>PMID:11598104</ref> <ref>PMID:11724780</ref> <ref>PMID:12065600</ref> <ref>PMID:14511394</ref> <ref>PMID:12740371</ref> <ref>PMID:14709557</ref> <ref>PMID:17341212</ref> <ref>PMID:21204788</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The AMP-activated protein kinase (AMPK) is a potential therapeutic target for metabolic diseases based on its reported actions in the liver and skeletal muscle. We evaluated two distinct direct activators of AMPK: a non-selective activator of all AMPK complexes, PF-739, and an activator selective for AMPK beta1-containing complexes, PF-249. In cells and animals, both compounds were effective at activating AMPK in hepatocytes, but only PF-739 was capable of activating AMPK in skeletal muscle. In diabetic mice, PF-739, but not PF-249, caused a rapid lowering of plasma glucose levels that was diminished in the absence of skeletal muscle, but not liver, AMPK heterotrimers and was the result of an increase in systemic glucose disposal with no impact on hepatic glucose production. Studies of PF-739 in cynomolgus monkeys confirmed translation of the glucose lowering and established activation of AMPK in skeletal muscle as a potential therapeutic approach to treat diabetic patients.

Activation of Skeletal Muscle AMPK Promotes Glucose Disposal and Glucose Lowering in Non-human Primates and Mice.,Cokorinos EC, Delmore J, Reyes AR, Albuquerque B, Kjobsted R, Jorgensen NO, Tran JL, Jatkar A, Cialdea K, Esquejo RM, Meissen J, Calabrese MF, Cordes J, Moccia R, Tess D, Salatto CT, Coskran TM, Opsahl AC, Flynn D, Blatnik M, Li W, Kindt E, Foretz M, Viollet B, Ward J, Kurumbail RG, Kalgutkar AS, Wojtaszewski JFP, Cameron KO, Miller RA Cell Metab. 2017 May 2;25(5):1147-1159.e10. doi: 10.1016/j.cmet.2017.04.010. PMID:28467931<ref>PMID:28467931</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5ufu" style="background-color:#fffaf0;"></div>

==See Also==
*[[AMP-activated protein kinase 3D structures|AMP-activated protein kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Rattus norvegicus]]
[[Category: Calabrese MF]]
[[Category: Kurumbail RG]]